Background: Cervical cancer is the second most common cancer among Indian women. This present retrospective study was conducted to report patient outcomes with locally advanced cervical cancer treated in the year 2010. Materials and Methods: Case records of cervical cancer patients registered from January 1, 2010, to December 31, 2010 were retrieved. A total of 1200 patients were registered, of which 583 received either definitive or adjuvant radiotherapy (RT). Of these, 345 patients who received complete treatment at our hospital were included for outcome analysis. Descriptive statistics were used to summarize patient- and treatment-related variables, and Kaplan–Meier analysis was performed for survival analysis. Results: The median age was 56 years (range: 33–90). Squamous carcinoma was the most common histology (91.4%) and the majority were FIGO Stage III (45.4%). Median follow-up of the cohort was 44 months (1–85 months). The 5-year disease-free survival (DFS) across stages was 50%. Most important predictor of DFS was FIGO staging (Stage II vs. Stage III: 62% vs. 45%) and use of concurrent chemoradiotherapy (CTRT) l (RT vs. CTRT: 32% vs. 57%, respectively). Patients aged >70 years had a significantly poor DFS at 5 years; however, did not have any effect on survival. Grade 3 or more late toxicity was seen in only 5% of the patients. Conclusion: Five-year DFS of 62% and 45% of Stage II and III patients treated under routine care represents comparable stage-matched results to the rest of the world, respectively.

Cervical cancer is the second most common cancer in Indian women.[1] India accounts for almost one-fourth of cervical cancer incidence and deaths.[2] Locally advanced stage at presentation is associated with high mortality.[3] As concurrent chemoradiation is the backbone of curative treatment of locally advanced cervical cancers, much of the thrust of the treatment lies in providing adequate facilities for good-quality external radiation, brachytherapy, and delivery of adequate concurrent chemotherapy. Several studies from the Western world have demonstrated the importance of the quality of radiotherapy (RT) in providing better cure rates in cervical cancer, whether it is the importance of overall treatment time,[4] or the number of cycles of concurrent chemotherapy delivered, or the importance of CT-based planning in the outcomes.[5]

The National Cancer Grid of India[6] aims to offer uniform treatment to cancer patients across India. With one of the aims of the program being to “evolve and implement a uniform standard of cancer care across India,” as a key institution under the program, it is fitting to take a step back and study outcomes of patients treated under routine clinical conditions at our institution. This retrospective clinical study was performed to report outcomes following radiation for locally advanced cervical cancer.

» Materials and Methods

Cervical Cancer patients who were registered at Tata Memorial Centre from January 1, 2010, to December 31, 2010, with a diagnosis of locally advanced cervical cancer, and who received radiation with or without concurrent chemotherapy were eligible for this retrospective study. Case records of all patients registered in the Gynecology Disease Management Group were retrieved from the hospital information system. The electronic medical records and case files of these patients were examined, and demographic information as well as information regarding stage, histology, and treatment offered was retrieved. Follow-up data were retrieved through case records or follow-up telephonic calls.

Treatment policies for patients treated with radiation in 2010

All treatment decisions were made within the multidisciplinary clinic after clinical evaluation, biopsy, and other staging investigations. For locally advanced cervical cancer, a majority of patients underwent ultrasonography of the abdomen and pelvis at the baseline. Routine contrast-enhanced computed tomography and magnetic resonance imaging (MRI) was not performed. The therapeutic decisions were made according to evidence-based guidelines published by the hospital with individualized modifications made on case-to-case basis if necessary.

A total of 40 Gy in 20 fractions was delivered through external beam radiation therapy (EBRT) to the whole pelvis followed by weekly HDR intracavitary brachytherapy applications of 7 Gy each to point A for 5 fractions. A customized midline shield was used in the anterior and posterior beams to block the central organs. Patients eligible for concurrent chemotherapy received weekly cisplatin (40 mg/m2) during external radiation therapy.

Patients with minimal involvement (<1 cm) of the bladder or rectal mucosa were considered for chemoradiotherapy. Few patients were considered for neoadjuvant chemotherapy (paclitaxel/carboplatin 2–4 cycles) followed by assessment for radical therapy if response was favorable. All others were given palliative RT (30 Gy/3 fractions/3 months). The decision for treatment was at the discretion of the treating physician and multidisciplinary discussion.

All patients treated with radical intent received a cumulative dose of 70–78 Gy equivalent doses in 2 Gy (EQD2) to point A.

Radiotherapy portals

Adjuvant radiotherapy

The anteroposterior portals included pelvis from L5-S1 to obturator foramen or covering upper third vagina and laterally to cover 1.5–2 cm lateral to pelvic brim. Four-field technique was used when separation at midpelvis was >20 cm.

Radical radiotherapy

The portals included pelvis from L5-S1 to obturator foramen or 2–3 cm inferior to lower vaginal disease and 1.5–2 cm lateral to pelvic brim. In node-positive patients, upper field border was extended to the L4/L5 junction. Medial or involved inguinal nodes were included in patients with Stage IIIA disease or with Stage IIIB and involvement of lower third. Four-field technique was used when separation at midpelvis was >20 cm.

Follow-up

All patients were followed up with physical examination every 3 months for the first 2 years, 6 months for the next 3 years, and yearly thereafter. Imaging was symptom directed and was performed at the discretion of the physician.

Statistical (outcome) analysis

Demographic details such as age, histology, and stage of the disease at diagnosis were retrieved. The treatment details including the intent and type of treatment were recorded. Further details regarding completion of planned treatment and disease status on follow-up were retrieved. For the analysis of disease-free survival (DFS), the date of histopathological diagnosis and last follow-up were utilized. Further telephonic follow-up was done to ascertain the recent status of disease or date of death wherever applicable. DFS was defined from the date of diagnosis to the date of recurrence or death due to any cause. Patients lost within 3 years of treatment completion were considered to have “event” for DFS analysis. DFS was further analyzed according to known patient-, treatment-, and tumor-related prognostic factors.

» Results

A total of 1200 patients with cervical cancer were registered in 2010, of which 853 were considered for treatment at our institution. [Table 1] shows the demographic profile of patients considered fit for radical treatment. Of the 853 patients, 584 were recommended definitive radiation therapy and 58/112 operated patients received adjuvant RT. Therefore, overall, approximately 75 % patients were recommended some form of radiation. Of the 642 patients who warranted radiation therapy, only 443 received treatment at our institute and the rest were referred outside owing to a long waiting list. Of the 443 patients, staging and treatment details were missing for 31 patients and 67 patients, resulting in 345 patients for final analysis. [Table 2] shows stage-wise treatment allocation to patients.

The median age was 56 years (range: 33–90) with squamous carcinoma as the most common histology (91.4%) followed by adenocarcinoma or adenosquamous carcinoma or undifferentiated histology in 6.4% and 2%, respectively. Majority of the patients had Stage III disease (45.4%) and a small proportion, who were Stage IV (5%), were also treated with radical radiation therapy. [Table 3] shows the stage-wise distribution of patients who received RT.

The median follow-up of the entire cohort was 44 months (1–85 months) and 64 months for surviving patients (56–64 months). Overall, 34/345 (10%) patients were lost to follow-up within 3 years of treatment completion and another 7% after 3 years of treatment completion. The 5-year DFS of the cohort was 50% [Figure 1], presuming that the patients who were lost to follow-up within the 3-year period would have had a disease-related event. Therefore, our outcomes represent conservative figures. However, if 50% of those lost to follow-up are presumed to be event free, then the real 5-year DFS would be between 53% and 55%.

Patients with age <70 years had a significant better DFS than the patients with age >70 years (P = 0.04).

Histology

There was no significant difference in DFS based on histology type (P = 0.4).

Multivariate analysis

Due to lack of complete information on other predictive and prognostic factors such as tumor volume, nodal stage, overall treatment time, and chemotherapy dose intensity, multivariate analysis was not performed.

» Discussion

The present report of 5-year outcomes of patients with locally advanced cervical cancer represents outcomes of all patients treated with radical conventional chemoradiation and X-ray-based brachytherapy. A 5-year DFS of 62% and 45% was reported in Stage II and Stage III with a median follow-up approximately 4 years, respectively. Using the method for outcome analysis where we assumed patients lost to follow-up within 3 years of treatment as an “event” for DFS analysis, we report that 50% of our patients were disease free at 5 years. However, adjusting DFS according to the observed 50% event rate, the real DFS may be approximately 67% and 50% for Stage II and Stage III, respectively, which is superior to 5-year outcomes reported from our institution in the late 1990s when the standard treatment was RT alone.[7] These DFS outcomes are very gratifying as they are almost similar to patients treated within clinical trials in our institute for Stage II B and III B, respectively, during the same period with RT doses of 70–78 Gy EQD2 to point A.[8],[9] It is noteworthy that these patients were treated with megavoltage radiation using conventional external radiation and X-ray-based brachytherapy and none of them underwent advanced imaging (such as MRI) integrated for their treatment planning or execution.

We also observed significantly improved outcomes with the use of concurrent chemotherapy; however, the large magnitude of observed difference may be attributed to confounders such as case selection for chemotherapy, stage of disease at presentation (which may be less advanced in those receiving concurrent chemotherapy), total EQD2 delivered, and other comorbidities. It is also noteworthy that, in 2010, all patients underwent ultrasonography prior to chemoradiation and there could be an imbalance between the two cohorts regarding nodal positivity.

As this was a retrospective analysis, detailed data regarding compliance to treatment (both radiation and chemotherapy) could not be retrieved, which limits us from undertaking a detailed analysis of the impact of compliance on DFS as well as acute and late toxicity. However, in a recent study undertaken in our institute for patients treated in the year 2014, we observed that up to 82% patients with locally advanced cervical cancer were fit to receive concurrent chemotherapy. Of these, 71% received 4 or more cycles. Overall, only 48% patients could receive the recommended 5 cycles of chemotherapy. Overall, >95% patients completed planned external radiation and brachytherapy.

We observed grade III or higher gastrointestinal or genitourinary toxicity in 5% of patients.

In recent years, improved local control has been reported with integration of image guidance and dose escalation to gross tumor and high-risk clinical target volume, as in the EMBRACE study; however, in a recent report by RetroEMBRACE that had image guidance but no dose escalation, 5-year OS of 70% and 42% was noted in Stage IIB and IIIB, respectively.[10] In a SEER analysis of 3246 patients treated with chemoradiation and brachytherapy during 2000–2009,[11] 5-year OS of 54% was reported and a similar 5-year survival of 54% was reported by the National Cancer Database of 2446 patients treated after integrating advanced imaging in the USA.[12] In the present series, unadjusted 5-year DFS was 50% which is comparable to stage-matched patients treated in other parts of the world.

The strengths of the present retrospective study are the reported comparable stage-matched clinical outcomes of patients treated under routine care in a tertiary care hospital in India. However, due to lack of details regarding nodal status, tumor volume, and chemotherapy dose intensity, a detailed prognostic analysis could not be undertaken. While overall therapeutic ratio can be improved by integrating advanced radiation techniques or treatment concepts, its impact on DFS or OS remains to be assessed. Many investigator-initiated or multicentric international clinical trials at our center are investigating the impact of advanced RT techniques and integration of systemic treatment[8],[9],[10],[11],[12],[13],[14],[15],[16],[17],[18],[19],[20] for improving DFS and OS and the results will guide our future practice.

» Conclusions

Five-year outcomes of locally advanced cervical cancer treated in routine clinical practice are similar to those reported internationally. Institutional audits during treatment and at regular intervals may assist the identification of key lacunae in treatment delivery which may further assist in improving outcomes.